The concept of lead-oriented synthesis (LOS) seeks to address to the paucity of diverse compounds with appropriate properties for biological screening. This thesis focuses on the preparation of diverse scaffolds, which, following decoration, may provide access to lead-like compounds. Key polyfunctionalised building blocks were prepared to enable the synthesis of such scaffolds by applying small tool-kits of robust synthetic methodologies. Computational tools were used to guide the development of key methodologies and to target the preparation of specific scaffolds. In addition, computational tools were used to retrospectively analyse the ability of the scaffolds prepared to provide access to lead-like space. Chapter 1 discusses ideal molecular properties for drugs and leads, modern synthetic approaches to the preparation of diverse screening compounds, and the emergence of LOS as a concept to resolve the challenge of sourcing large numbers of ideal screening compounds. Chapter 2 details the preparation of small polyfunctionalised building blocks through the allylation of amino acid-derivatives. A building-up (‘bottom-up’) approach was used to prepare scaffolds, exploiting the intramolecular capture of pendant nucleophiles at alkene or ester functionalities, and the use of transition metal-catalysed cyclisations. Four building blocks were used to prepare 22 scaffolds. A virtual library of 1110 compounds was enumerated from the scaffolds, of which 66% were found to be lead-like. Chapter 3 describes the preparation of larger polycycles using an intramolecular [5+2] oxidopyrylium cycloaddition. The two polycyclic assemblies prepared were deconstructed using a ‘top-down’ approach to give six scaffolds. A virtual library of 798 compounds was enumerated from the scaffolds, of which 72% would be lead-like. Chapter 4 compares the value of the different LOS approaches developed, this considers the ability of the scaffolds to provide access to lead-like space, their three-dimensionality, and the synthetic economy of their preparation.